Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents.

Julia Krzywik,Witold Mozga,Adam Huczyński,Joanna Wietrzyk,Ewa Maj,Jack A Tuszyński,Jan Janczak,Maral Aminpour

doi:10.3390/molecules25081789

Abstract

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.

Highlights

Microtubules, which are composed of α- and β-tubulin heterodimers, are involved in a large number of processes, such as intracellular transport, cell shape development, cell division and cell motility
We report the synthesis, crystallographic and spectroscopic analysis of a series of structurally different derivatives of colchicine obtained by its modification at position C7 and at position C10
The general route for the synthesis of colchicine derivatives 2–21 is depicted in Scheme 1

Summary

Introduction

Microtubules, which are composed of α- and β-tubulin heterodimers, are involved in a large number of processes, such as intracellular transport, cell shape development, cell division and cell motility. Many inhibitors of microtubule dynamics have been investigated for their potential use as cancer chemotherapy drugs [1,2,3,4,5,6,7]. One of these compounds is colchicine 1 (see Scheme 1), a well–known tropolone alkaloid isolated from Colchicum autumnale, which has been shown to exhibit very high cytotoxic effects. It binds to tubulin at the colchicine binding

Methods

Results

Conclusion